Disease Activity-Free Status in CARE-MS I Phase 3 Study
G Giovannoni, DL Arnold, JA Cohen, AJ Coles, C Confavreux, EJ Fox, HP Hartung, E Havrdova, K Selmaj, H Weiner, V Brinar, M Stojanovic, SL Lake,
DH Margolin, M Panzara, M Rizzo, and DAS Compston
for the CARE-MS I investigators
2
Disclosures
Dr Gavin Giovannoni reports receiving personal compensation for participating on advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from Bayer-Schering Healthcare, Biogen Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GlaxoSmithKline, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva Pharmaceuticals, UCB Pharma, and Vertex Pharmaceuticals.
Dr Douglas L. Arnold reports receiving personal compensation or research support form Bayer Healthcare, Biogen Idec, Genentech, Genzyme, Roche, and Teva Pharmaceuticals.
Dr Jeffrey Cohen reports receiving personal compensation as a consultant or speaker from Biogen Idec, Eli Lilly, Novartis, Teva Pharmaceuticals, Receptos, and Vaccinex.
Dr Alasdair J. Coles reports receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck-Serono, and UCB-Celltech.
Prof Christian Confavreux reports receiving research support from Bayer-Schering, Biogen Idec, Genzyme, Merck-Serono, Novartis, Sanofi-Aventis and Teva Pharmaceuticals.
Dr Edward Fox reports receiving consultancy fees, honoraria, travel, and research support from Bayer Healthcare, Novartis, Ono, Sanofi-Aventis, Biogen Idec, EMD Serono, Genzyme, Opexa Therapeutics, Pfizer, Teva Pharmaceuticals, and Eli Lilly.
Dr Hans-Peter Hartung reports receiving the approval of the Rector of HHU fees for consulting, lectures, and activities in Steering Committees of the following companies: Bayer Schering, Biogen Idec, BioMS, Genzyme, Merck-Serono, Novartis, Teva Pharmaceuticals, and Sanofi-Aventis.
Prof Eva Havrdova reports receiving honoraria and grant support from Bayer-Schering, Biogen Idec, Genentech, Genzyme, GlaxoSmithKline, Merck-Serono, Octapharma, Pfizer, Roche, Sanofi-Aventis, and Teva Pharmaceuticals.
CARE-MS I
Dr Krzysztof Selmaj reports receiving consulting fees from Genzyme, Novartis, Biogen Idec, and Roche; lecture fees from Novartis, Merck-Serono, Biogen Idec, and Bayer Healthcare; and financial compensation, including travel, from Genzyme for scientific presentations.
Dr Howard Weiner reports receiving consulting/honoraria from Biogen Idec, EMD Serono, Genzyme, Teva Pharmaceuticals, Novartis, Nasvax, and GlaxoSmithKline and research support from EMD Serono and GlaxoSmithKline.
Dr Gavin Giovannoni reports receiving personal compensation for participating on advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from Bayer-Schering Healthcare, Biogen Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GlaxoSmithKline, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva Pharmaceuticals, UCB Pharma, and Vertex Pharmaceuticals.
Prof Alastair Compston reports receiving consulting fees, lecture fees, and grant support from Genzyme and lecture fees from Bayer Schering Pharma on behalf of the University of Cambridge.
Drs Vesna Brinar and Miroslav Stojanovic report no conflicts of interest.
Drs David H. Margolin, Stephen L. Lake, and Michael Panzara report receiving personal compensation as employees of Genzyme, a Sanofi company.
Funding was provided by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals.
3
Anti CD52 mAb: humanized monoclonal antibody
Targets CD52 causing depletion of circulating B and T lymphocytes
The acute anti-inflammatory effect is immediately followed by a distinctive pattern of repopulation that occurs over time
This repopulation creates a rebalanced immune system; this mechanism may explain how anti CD52 mAb reduces MS disease activity
Anti CD52 mAb has minimal impact on other immune cells
White Blood Counts after Anti CD52 mAb in CARE-MS I
Neutrophils
MonocytesEosinophilsBasophils
Lymphocytes
0.0
0.5
1.0
1.5
2.0
4.0
4.5
5.0
0 1 2 3 4 5 6 7 8 9 10 11 12C
ell
Co
un
ts (
109
/L)
Months after Anti CD52 mAb
CARE-MS I
4
Background and Objective
Two successful phase 3 clinical trials for relapsing-remitting MS (RRMS) vs. subcutaneous interferon beta-1a (SC IFNB-1a)
– CARE-MS I (treatment-naïve patients):• Relapse rate reduced by 55% (p<0.0001)• No significant reduction in sustained accumulation of disability (SAD) (p=0.22)
– CARE-MS II (patients active on prior treatment):• Relapse rate reduced by 49% (p<0.0001) • Risk of SAD reduced by 42% (p=0.0084)
Objective: compare the effects of anti CD52 mAb and SC IFNB-1a on the proportion of patients free of MS disease activity in CARE-MS I (tertiary endpoint)
CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple SclerosisCARE-MS I
55
CARE-MS I: Study Design
Two-year, randomized, rater-blinded, global, multicenter trial
Key inclusion criteria:– Treatment-naïve RRMS– ≥ 2 relapses in last 2 years; ≥1 relapse in last year– EDSS 0–3 – Disease onset <5 years
CARE-MS I
n=173
n=367n=367
3x/week
Anti CD52 mAb12 mg IV(n=376)
IFNB-1a44 mcg SC(n=187)
Daily x 5
Daily x 3
Study duration (months)
0 12 24
Randomized 2:1 (N=581)
Randomized 2:1 (N=581)
6
Measurements of Disease Activity in MS
Relapse– Symptoms must be attributable to MS, last at least 48 hours, be present at
normal body temperature, and be preceded by at least 1 month (30 days) of clinical stability
– Assessed by blinded raters; Relapse Adjudication Panel
6-Month Sustained Accumulation of Disability (SAD)– Increase of ≥1.0 points for ≥6 months, or 1.5 points if baseline EDSS = 0– Blinded raters assessed EDSS at baseline and every 3 months
MRI– New or enlarging T2 lesions or new gadolinium-enhancing lesions– Cranial MRI performed at baseline and annually; scans read by blinded
neuro-radiologists at independent center
CARE-MS I
7
Disease-Free Composite Endpoints
Clinical Disease Activity (CDA)-free: absence of relapse or SAD
MRI Activity-free: absence of new Gd-enhancing lesion or new or enlarging T2 hyperintense lesion
MS Disease Activity-free: absence of CDA or MRI activity
CARE-MS I
8
Relapse-free
78%
59%55% Risk Reductionp<0.0001
Follow-up Month
Pat
ien
ts w
ith
ou
t R
elap
se (
%) 100
85
75
65
500 3 6 9 12 15 18 21 24
187 175 156 137 127 118 116 109 101376 366 358 340 321 313 306 299 287
SC IFNB-1aAnti CD52 mAb
No. of Observations
95
80
70
60
90
55
CARE-MS I
9
6-month SAD-free
Unexpectedly low rate of SAD events in the SC IFNB-1a armUnexpectedly low rate of SAD events in the SC IFNB-1a arm
CARE-MS I
100
94
86
80
90
88
96
84
92
98
82
89%89%
92%92%
Follow-up Month
Pat
ien
ts w
ith
ou
t S
AD
(%
)
0 3 6 9 12 15 18 21 24
187 185 181 177 170 164 162 158 149376 376 372 368 363 357 352 345 336
SC IFNB-1aAnti CD52 mAb
No. of Observations
p=0.22
SC IFNB-1aAnti CD52 mAb
10
Clinical Disease Activity-free at Year 2
Odds of experiencing CDA 2.4 times higher with SC IFNB‑1a vs. Anti CD52 mAb; odds ratio = 2.36 (95% confidence interval [CI]: 1.62, 3.43),
CARE-MS I
p<0.0001
p=0.2173
p<0.0001
SC IFNB-1aAnti CD52 mAb
11
MRI Activity-free at Year 2
CARE-MS I
No New/Enlarging T2
LesionsNo Gd-Enhancing
LesionsMRI Activity-Free
p=0.0352
p=0.0008
p=0.0388
SC IFNB-1aAnti CD52 mAb
12
MS Disease Activity-free at Year 2
• Odds of experiencing MS disease activity 1.75 times higher with SC IFNB-1a vs. Anti CD52 mAb; odds ratio=1.75 (95% CI: 1.17, 2.61)
CARE-MS I
CDA-Free MRI Activity–Free MS Disease Activity-Free
p<0.0001
p=0.0388
p=0.0064
SC IFNB-1aAnti CD52 mAb
13
Number of Measures of Disease Activity over 2 Years
CARE-MS I
• Measures of disease activity: relapse, SAD, T2 new/enlarging and Gd+T1 lesions
SC IFNB-1aAnti CD52 mAb
14
Safety Summary
Infusion-associated reactions (IARs)– 90% of anti CD52 mAb patients– Commonly included headache, rash, pyrexia, urticaria, flushing and chills– Responsive to premedication– Few serious IARs; and only 1 patient discontinued treatment due to IAR
Infections – 67% anti CD52 mAb vs. 46% SC IFNB-1a; mostly mild to moderate severity, none
life-threatening or fatal – Most common infections included upper respiratory, UTI, herpes, and localized
fungal– Few serious infections (1.9% anti CD52 mAb vs. 1.1% SC IFNB-1a)
Autoimmune events– Thyroid disorders (18% anti CD52 mAb vs. 6.4% SC IFNB-1a), few serious (1% anti
CD52 mAb vs. 0% SC IFNB-1a), detected through regular monitoring; most events managed by conventional oral medications
– Immune Thrombocytopenic Purpura (0.8% Anti CD52 mAb vs. 0.5% SC IFNB-1a)– Risk minimization plan (patient and physician education, monthly questionnaires,
and monthly labs) allowed early detection and intervention
CARE-MS I
15
Conclusions
CARE-MS I
Freedom from disease activity is an important treatment goal in active relapsing-remitting MS
In an active, early, treatment-naïve population, anti CD52 mAb-treated patients were more likely to be free of clinical disease activity, MRI activity, and overall disease activity than SC IFNB-1a-treated patients
These results reinforce and extend previously reported superior efficacy of anti CD52 mAb over SC IFNB-1a
Safety profile for anti CD52 mAb was consistent with prior studies
The benefit-risk profile of anti CD52 mAb suggests that it may be an effective treatment option in active, early, treatment-naive RRMS patients
16
CARE-MS I Study Group and Acknowledgments
ArgentinaDeri
AustraliaBroadleyBoundyDreyerKingMacdonellMcCombePaineReddelVucic
Brazil CallegaroMartins
CanadaFreedmanGrand’MaisonJacquesTraboulseeYeung
CroatiaAntonelliBrinarHabekKidemet-PiskaćTrkanjecVladic
Czech RepublicKovarovaVachova
SerbiaDinčićDrulovićNadjStojanovićVojinović
SwedenLycke
UkraineKobysMartsynkevychNehrychOrzheshkovskyiVoloshyna
United KingdomColesCompston GiovannoniRobertsonSharrack
United StatesBassBomprezziBosterBraleyCarterCascioneEdwardsFoxGazda GoodmanGudesblattGupta
United States (cont)HerbertHunterHuttonIoneteJonesKaufman KhanLaGanke LallanaLynchMillerMinagarPardoRoweSheppardSteingoTwymanVaishnavVincentWendtWrayWynn
GenzymeBachtellHollensteinJurgensenLakeMargolinMercerOyuelaPalmerPanzaraRizzoSaltonstallSmith
Neurology Steering CommitteeCompston (UK)Arnold (CA)Cohen (US)Coles (UK)Confavreux (FR)Fox (US)Hartung (DE)Havrdova (CZ)Selmaj (PL)Weiner (US)
Data Monitoring CommitteeClifford (US)Barkhof (ND)Snydman (US)DeGroot (US)Cines (US)D’Agostino (US)Antel (CA)Panitch (US) (in memoriam)
Relapse Adjudication PanelGreenberg (US)Kraus (AT)Limmroth (DE)Markowitz (US)Naismith (US)Tabby (US)
MRI AnalysesArnold; NeuroRX (CA)Fisher; CCF (US)
FranceClanet
GermanyBaumHaasStangelZiemannZiemssen
MexicoSantosViolante
PolandKozubskiSelmajStelmasiakSzczudlik
Russia BarantsevichBelovaBoykoGusevMishinMagzhanovMalkovaPoverennovaSkorometsStolyarovYakupovZavalishin
CARE-MS I